Drug Targeting Organ-Specific Strategies

182 7 Vascular Endothelium in Inflamed Tissue as a Target for Site Selective Delivery of Drugs
ically derived peptide dimer [74]. Recently, Storgard and colleagues demonstrated that
monocyclic RGDfV peptides target the synovial blood vessels in antigen-induced arthritis in
rabbits [36]. A general consideration concerning peptides is the relatively short half-life of
these molecules compared to larger proteins [75]. Whether this is an advantage or disadvantage
depends on the application. For nuclear imaging purposes a short half-life is favourable,
whereas a longer circulation time would be useful for therapeutic purposes.
Peptides as well as oligosaccharides (discussed below) that specifically bind to molecules
on the endothelium may be used as homing ligands in larger constructs. Covalent attachment
to e.g. a protein backbone or liposomes may lead to carriers with multivalent binding sites.
Furthermore, drug loading of the peptide/oligosaccharide-modified carrier can be increased,
in contrast to the 1 : 1 ratio in the case of direct coupling of the drug to the peptide or
oligosaccharide.
7.4.2.3 Oligosaccharides
Selectins mediate contact by binding to carbohydrate-containing receptors on leucocytes
through their N-terminal lectin domain. Sialyl-Lewis X (Neu5Acα2-3-Galβ1-4(Fucα1-3)Glc-
NAc) and derivatives thereof were shown to bind to the selectins and subsequently inhibit ischaemia-induced
leucocyte infiltration in the liver [76–78]. A similar compound prevented
antigen-induced late bronchial responses and airway hyper-responsiveness in allergic sheep
[79].
The binding potency of the native sialyl-Lewis X can be increased with three orders of
magnitudes by conjugating this saccharide to BSA. This is probably due to the clustering of
saccharides that may favour binding to E-selectin [80].
It should be borne in mind, that targeting the selectins with Sialyl-Lewis X-derived homing
devices will not result in selective targeting to the endothelium. As well as the activated
endothelium, naïve T-lymphocytes bearing L-selectin will also be a target for such a preparation.Whether
this poses a problem by creating a site of non-target cell binding and hence loss
of the drug targeting preparation, or whether it is beneficial from a therapeutic point of view
because it may inhibit T cell activation, remains to be investigated.
7.4.3 Drugs Inhibiting Endothelial Activation
7.4.3.1 Inhibitors of NFκB and Other Intracellular Signalling Pathways
Based on its central role in pro-inflammatory reactions, the transcription factor NFκB has attracted
much of attention as a target for therapeutic intervention. Drugs like pyrrolidine
dithiocarbamate (PDTC), N-acetylcysteine or α-tocopheryl succinate prevent IκB degradation,
thereby stabilizing the NFκB complex and inhibiting cytokine production, adhesion
molecule expression and preventing vascular injury both in vitro and in vivo [81–86]. However,
these drugs work in a rather non-specific fashion since they influence general cellular
mechanisms such as the redox state and proteasome function.